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SHR Neuro Cancer Cardio Lipid Metab Microb

Klaiber, M; Dankworth, B; Kruse, M; Hartmann, M; Nikolaev, VO; Yang, RB; Völker, K; Gassner, B; Oberwinkler, H; Feil, R; Freichel, M; Groschner, K; Skryabin, BV; Frantz, S; Birnbaumer, L; Pongs, O; Kuhn, M.
A cardiac pathway of cyclic GMP-independent signaling of guanylyl cyclase A, the receptor for atrial natriuretic peptide.
Proc Natl Acad Sci U S A. 2011; 108(45):18500-18505 Doi: 10.1073/pnas.1103300108 [OPEN ACCESS]
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Co-authors Med Uni Graz: Groschner Klaus
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Abstract:: Cardiac atrial natriuretic peptide (ANP) regulates arterial blood pressure, moderates cardiomyocyte growth, and stimulates angiogenesis and metabolism. ANP binds to the transmembrane guanylyl cyclase (GC) receptor, GC-A, to exert its diverse functions. This process involves a cGMP-dependent signaling pathway preventing pathological [Ca(2+)](i) increases in myocytes. In chronic cardiac hypertrophy, however, ANP levels are markedly increased and GC-A/cGMP responses to ANP are blunted due to receptor desensitization. Here we show that, in this situation, ANP binding to GC-A stimulates a unique cGMP-independent signaling pathway in cardiac myocytes, resulting in pathologically elevated intracellular Ca(2+) levels. This pathway involves the activation of Ca(2+)-permeable transient receptor potential canonical 3/6 (TRPC3/C6) cation channels by GC-A, which forms a stable complex with TRPC3/C6 channels. Our results indicate that the resulting cation influx activates voltage-dependent L-type Ca(2+) channels and ultimately increases myocyte Ca(2)(+)(i) levels. These observations reveal a dual role of the ANP/GC-A-signaling pathway in the regulation of cardiac myocyte Ca(2+)(i) homeostasis. Under physiological conditions, activation of a cGMP-dependent pathway moderates the Ca(2+)(i)-enhancing action of hypertrophic factors such as angiotensin II. By contrast, a cGMP-independent pathway predominates under pathophysiological conditions when GC-A is desensitized by high ANP levels. The concomitant rise in [Ca(2+)](i) might increase the propensity to cardiac hypertrophy and arrhythmias.
Find related publications in this database (using NLM MeSH Indexing): Animals -; Atrial Natriuretic Factor - metabolism; Cell Line -; Cyclic GMP - metabolism; Fluorescence Resonance Energy Transfer -; Guanylate Cyclase - metabolism; Humans -; Mice -; Myocardium - metabolism; Receptors, Atrial Natriuretic Factor - metabolism; Signal Transduction -